Identification of Novel T1D Risk Loci and Their Association With Age and Islet Function at Diagnosis in Autoantibody-Positive T1D Individuals: Based on a Two-Stage Genome-Wide Association Study

被引：88

作者：

Zhu, Meng ^{[1
,2
,3
]}

Xu, Kuanfeng ^{[1
]}

Chen, Yang ^{[1
]}

Gu, Yong ^{[1
]}

Zhang, Mei ^{[1
]}

Luo, Feihong ^{[4
]}

Liu, Yu ^{[5
]}

Gu, Wei ^{[6
]}

Hu, Ji ^{[7
]}

Xu, Haixia ^{[8
]}

Xie, Zhiguo ^{[9
,10
,11
]}

Sun, Chengjun ^{[4
]}

Li, Yuxiu ^{[12
]}

Sun, Min ^{[1
]}

Xu, Xinyu ^{[1
]}

Hsu, Hsiang-Ting ^{[1
]}

Chen, Heng ^{[1
]}

Fu, Qi ^{[1
]}

Shi, Yun ^{[1
]}

Xu, Jingjing ^{[1
]}

Ji, Li ^{[1
]}

Liu, Jin ^{[1
]}

Bian, Lingling ^{[1
]}

Zhu, Jing ^{[1
]}

Chen, Shuang ^{[1
]}

Xiao, Lei ^{[1
]}

Li, Xin ^{[1
]}

Jiang, Hemin ^{[1
]}

Shen, Min ^{[1
]}

Huang, Qianwen ^{[8
]}

Fang, Chen ^{[7
]}

Li, Xia ^{[9
,10
,11
]}

Huang, Gan ^{[9
,10
,11
]}

Fan, Jingyi ^{[2
]}

Jiang, Zhu ^{[2
]}

Jiang, Yue ^{[2
]}

Dai, Juncheng ^{[2
]}

Ma, Hongxia ^{[2
]}

Zheng, Shuai ^{[1
]}

Cai, Yun ^{[1
]}

Dai, Hao ^{[1
]}

Zheng, Xuqin ^{[1
]}

Zhou, Hongwen ^{[1
]}

Ni, Shining ^{[6
]}

Jin, Guangfu ^{[2
,3
]}

She, Jin-Xiong ^{[13
]}

Yu, Liping ^{[14
]}

Polychronakos, Constantin ^{[15
,16
]}

Hu, Zhibin ^{[2
,3
]}

Zhou, Zhiguang ^{[9
,10
,11
]}

机构：

[1] Nanjing Med Univ, Affiliated Hosp 1, Dept Endocrinol, Nanjing, Jiangsu, Peoples R China

[2] Nanjing Med Univ, State Key Lab Reprod Med, Ctr Global Hlth, Nanjing, Jiangsu, Peoples R China

[3] Nanjing Med Univ, Dept Epidemiol & Biostat, Sch Publ Hlth, Nanjing, Jiangsu, Peoples R China

[4] Fudan Univ, Childrens Hosp, Dept Pediat Endocrinol & Inherited Metab Dis, Shanghai, Peoples R China

[5] Nanjing Med Univ, Sir Run Run Hosp, Dept Endocrinol & Metab, Nanjing, Jiangsu, Peoples R China

[6] Nanjing Med Univ, Dept Endocrinol, Childrens Hosp, Nanjing, Jiangsu, Peoples R China

[7] Soochow Univ, Affiliated Hosp 2, Dept Endocrinol & Metab, Suzhou, Peoples R China

[8] Sun Yat Sen Univ, Affiliated Hosp 3, Guangdong Prov Key Lab Diabetol, Dept Endocrinol & Metab, Guangzhou, Guangdong, Peoples R China

[9] Cent S Univ, Xiangya Hosp 2, Dept Metab & Endocrinol, Changsha, Hunan, Peoples R China

[10] Natl Clin Res Ctr Metab Dis, Changsha, Hunan, Peoples R China

[11] Cent S Univ, Key Lab Diabet Immunol, Minist Educ, Changsha, Hunan, Peoples R China

[12] Chinese Acad Med Sci, Peking Union Med Coll, Peking Union Med Coll Hosp, Minist Hlth,Dept Endocrinol,Key Lab Endocrinol, Beijing, Peoples R China

[13] Augusta Univ, Med Coll Georgia, Ctr Biotechnol & Genom Med, Augusta, GA USA

[14] Univ Colorado Denver, Barbara Davis Ctr Childhood Diabet, Aurora, CO USA

[15] McGill Univ, Hlth Ctr Res Inst, Endocrine Genet Lab, Child Hlth & Human Dev Program, Montreal, PQ, Canada

[16] McGill Univ, Hlth Ctr Res Inst, Dept Pediat, Montreal, PQ, Canada

[17] Nanjing Med Univ, Key Lab Human Funct Genom Jiangsu Prov, Nanjing, Jiangsu, Peoples R China

来源：

DIABETES CARE | 2019年 / 42卷 / 08期

基金：

中国国家自然科学基金;

关键词：

DELTA T-CELLS; SUSCEPTIBILITY LOCI; TYPE-1; VARIANTS; COLOCALIZATION; AUTOIMMUNE; EFFECTORS; ANTIGENS; DISEASES; GENES;

D O I：

10.2337/dc18-2023

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

OBJECTIVE Type 1 diabetes (T1D) is a highly heritable disease with much lower incidence but more adult-onset cases in the Chinese population. Although genome-wide association studies (GWAS) have identified >60 T1D loci in Caucasians, less is known in Asians. RESEARCH DESIGN AND METHODS We performed the first two-stage GWAS of T1D using 2,596 autoantibody-positive T1D case subjects and 5,082 control subjects in a Chinese Han population and evaluated the associations between the identified T1D risk loci and age and fasting C-peptide levels at T1D diagnosis. RESULTS We observed a high genetic correlation between children/adolescents and adult T1D case subjects (r(g) = 0.87), as well as subgroups of autoantibody status (r(g) >= 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near BTN3A1 (odds ratio [OR] 1.26, P = 2.70 x 10(-8)) and rs3802604 in GATA3 (OR 1.24, P = 2.06 x 10(-8)), and two previously reported loci, rs1770 in MHC (OR 4.28, P = 2.25 x 10(-232)) and rs705699 in SUOX (OR 1.46, P = 7.48 x 10(-20)). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus P = 9.78 x 10(-12)), specific to the Chinese population. Based on the identified eight variants, we achieved an area under the curve value of 0.86 (95% CI 0.85-0.88). By building a genetic risk score (GRS) with these variants, we observed that the higher GRS were associated with an earlier age of T1D diagnosis (P = 9.08 x 10(-11)) and lower fasting C-peptide levels (P = 7.19 x 10(-3)) in individuals newly diagnosed with T1D. CONCLUSIONS Our results extend current knowledge on genetic contributions to T1D risk. Further investigations in different populations are needed for genetic heterogeneity and subsequent precision medicine.

引用

页码：1414 / 1421

页数：8

共 27 条

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